Method for preparing thiamine salts

ABSTRACT

THIAMINE SALTS OF HIGH PURITY ARE OBTAINED BY TREATING THIAMINE MONOTHIOCYANATE WITH HYDROCHLORIC ACID OR NITRIC ACID AND HEATING THE MIXTURE UNDER REDUCED PRESSURE UNTIL THE PRODUCED HYDROGEN MONOTHIOCYANATE IS EXPELLED FROM THE REACTION MIXTURE.

United States Patent METHOD FOR PREPARING THIAMINE SALTS Hozumi Tanaka,Ashiya, Kenji Ikawa, Osaka, and Fumitaka Takami, Higashiosaka, Japan,assignors to Shionogi & Co., Ltd., Osaka, Japan No Drawing.Continuation-impart of abandoned application Ser. No. 8,427, Feb. 3,1970. This application June 2, 1972, Ser. No. 259,303

Claims priority, application Japan, Feb. 25, 1969,

4/ 14,103 Int. Cl. C07d 99/12 U.S. Cl. 260256.6 1 Claim ABSTRACT OF THEDISCLOSURE Thiamine salts of high purity are obtained by treatingthiamine monothiocyanate with hydrochloric acid or nitric acid andheating the mixture under reduced pressure until the produced hydrogenmonothiocyanate is expelled from the reaction mixture.

BACKGROUND OF THE INVENTION Field of the invention The present inventionis a continuation-in-part application of Ser. No. 8,427, filed on Feb.3, 1970 (now abandoned). The present invention generally relates to aprocess for preparing thiamine salts. Particularly, it is concerned witha process for preparing the thiamine salts by treating thiaminemonothiocyanate with hydrochloric acid or nitric acid and heating themixture under reduced pressure until the produced hydrogenmonothiocyanate is expelled from the reaction mixture.

Description of the prior art At present, most thiamine derivatives areprepared from 3-[2-methyl-4'-aminopyrimidyl-(5')]-methy1 4 methyl-S-Bhydroxyethyl-thiothazolone-(2) (hereinafter, referred to as SE and aprocess of oxidizing said SB, and then eliminating the sulfate ionremaining in the reaction mixture by converting the ion into bariumsulfate or by use of an ion exchange resin to obtain thiaminederivatives, is already known.

Complete removal of said sulfate ion with barium chloride is howeververy difficult in view of the critic-a1 amount of the chloride requiredfor the neutralization and, in addition to this, there is an adversetendency of lowering the purity of the end product due to thecontamination with barium salts. The employment of an ion exchange resinalso shows an adverse effect on the quality of the end product, forinstance, thiamine hydrochloride because the thiamine in the reactionsystem is decomposed during the prolonged time required forconcentrating the reaction solution which has once been diluted and forprecipitating the thiamine hydrochloride.

A process for deriving SB, into thiamine monothiocyanate in its firststep and then converting the monothiocyanate into the required thiaminesalts by the action of hydrochloric acid or nitric acid is proposed toinsure the purity of the product. This process, although it seems to beeasy at first sight, is, however, very difiicult to perform becausethiamine salts can be arranged in the order of decreasing solubility asfollows:

3,812,124 Patented May 21, 1974 and accordingly, a former one in theabove row can be passed to a latter one by means of simple doubledecomposition but not vice versa.

SUMMARY OF THE INVENTION It is the primary object of the presentinvention to provide a method of preparing thiamine salts. It is anotherobject of the present invention to provide a method of convertingthiamine monothiacyanate into the required thiamine salts of high purityby overcoming the aforedescribed difliculty.

These and other objects of the present invention and attendantadvantages thereof will be apparent to those who are conversant with theart to which the present invention pertains by the following detaileddisclosure in the specification as well as in the appended claims.

According to the present invention, the aforementioned difiiculty isobviated by providing a process for preparing thiamine salts comprising;treating thiamine monothiocyanate with hydrochloric acid or nitric acidand concentrating the mixture with heat under reduced pressure until theproduced hydrogen monothiocyanate is expelled from the mixture.

The reaction can preferably be performed at a bath temperature of about-80 C. under reduced pressure below about 25 mm. Hg abs. The reactionconditions need not be restrictive so long as the expelling of theformed hydrogen monothiocyanate may effectively be made. Although thereaction period may vary with the size of the reaction vessel and thereaction mixture, the reaction can usually be carried out in about 0.5-2hours.

The following examples are given for the purpose of illustration.

EXAMPLE 1 Thiamine monothiocyanate g.) is dissolved in 10% hydrochloricacid (250 g.) and the mixture is concentrated under reduced pressure(IO-20 mm. Hg abs.) at a bath temperature of 60-80 C. An addition ofwarmed ethanol effected when crystals begin to precipitate, acceleratesthe precipitation. Standing the reaction mixture overnight underice-cooling and a subsequent filtration of the mixture aiford's 57 g.(96%) of thiamine hydrochloride (M.P. 250 C., with decomposition).

Starting material (thiamine monothiocyanate) is prepared as follows:

To a solution of 30% hydrogen peroxide (71.4 g.)

diluted 'with water (170 ml.), there is added portionwise3-[2'-methyl-4'-aminopyrimidyl-(5')]-methyl 4methyl-5-fl-hydroxyethyl-thiothiazolone (2) (59.2 g.) while maintainingthe temperature of the solution at 20--25 C. The mixture is then stirredfor 1.5 hours at this temperature. It is thereafter cooled with ice and2 g. of manganese dioxide is incorporated therein, and further stirredfor 2 hours to decompose the remaining hydrogen peroxide. Treatment ofthe pale yellowish reaction mixture with decoloring charcoal make thesolution colorless and transparent. Addition of ammonium thiocyanate(18.3 g.) at 25-30" C. and a dropwise addition of 20% Na CO initiatesprecipitation of crystals of thiamine monothiocyahate. The dropwiseaddition continues until the mixture exhibits a pH of 6-7 and then it isice-cooled while being stirred for a few minutes. A water rinsing of theprecipitated crystals collected by filtration affords crystals (M.P.192-193 C., with decomposition) of thiamine monothiocyanate (63.5 g.,93%).

3 EXAMPLE 2 A reaction substantially the same as that described inExample 1 is performed. In this example, however, 37.71 g. (0.359 mol)of 60% nitric acid and 150 ml. of water in lieu of the hydrochloric acidof Example 1, are used for 60 g. (0.176 mol) of thiaminemonothiocyanate, and 61.7 g. (90%) of thiamine dinitrate (M.P. 162-165C.) is obtained as the product.

What we claim is:

1. A process for preparing thiamine hydrochloride comprising treatingthiamine monothiocyanate with hydrochloric acid and concentrating themixture with heat under reduced pressure of below 25 mm. Hg abs. untilthe produced hydrogen thiocyanate is expelled from the mixture at a bathtemperature of about 50-80 C.

10 RICHARD J. GALLAGHER, Primary Examiner us. c1. x11. 260-25 6.5 B

